Mismatches in DNA arise naturally as a result of replication errors, endogenous DNA damaging agents, and spontaneous processes such as cytosine deamination. The mismatch repair (MMR) pathway acts to correct mismatches before subsequent rounds of replication, reducing the number of DNA mismatches in the human genome from ˜1000 to ˜1. The loss of MMR carries dire consequences, including increased mutation rates, carcinogenesis, and resistance to a variety of clinical anti-cancer agents, such as anti-metabolites, DNA alkylators, and cisplatin. Indeed, deficiencies in MMR have been linked to a variety of cancers, in particular, nonhereditary colorectal carcinoma, and are also associated with resistance or tolerance to many common therapeutics. Furthermore, this resistance to commonly used agents leads to enrichment of MMR-deficient cells; roughly half of secondary leukemias show MMR-deficiency. These issues point to the need for a therapeutic agent that specifically targets MMR-deficient cells. Of course, any potential agent must first reach its target before it may bind.
To that end, metalloinsertors have been developed to target DNA mismatches in vitro. DNA mismatches, owing to their loss of hydrogen bonding and poor stacking, are destabilized relative to well matched DNA. It is this thermodynamic destabilization that allows for a means of targeting mismatches, since mismatches do not significantly perturb the structure of the B-form DNA duplex. However, while existing metalloinsertors have been used to detect the existence of DNA mismatches, to date, the existing metalloinsertors have not been shown to cause cell death.